World Health Oganization. Definition, Diagnosis, and Classification of Diabetes
Mellitus and Its Complications: Report of a WHO Consultation. Part I: Diagnosis and Classification
of Diabetes Mellitus.Geneva, Switzerland: World Health Organization; 1999.

Friedwald WT, Levy RJ, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol
in plasma without the use of the preparative ultracentrifuge. Clin Chem.1972;18:499-502.PubMed

Context The worldwide explosive increase in type 2 diabetes mellitus and its
cardiovascular morbidity are becoming major health concerns.

Objective To evaluate the effect of decreasing postprandial hyperglycemia with
acarbose, an α-glucosidase inhibitor, on the risk of cardiovascular
disease and hypertension in patients with impaired glucose tolerance (IGT).

Design, Setting, and Participants International, multicenter double-blind, placebo-controlled, randomized
trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark,
Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total
of 1429 patients with IGT were randomized with 61 patients (4%) excluded because
they did not have IGT or had no postrandomization data, leaving 1368 patients
for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated
with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2).
These patients were followed up for a mean (SD) of 3.3 (1.2) years.

Intervention Patients with IGT were randomized to receive either placebo (n = 715)
or 100 mg of acarbose 3 times a day (n = 714).

Results Three hundred forty-one patients (24%) discontinued their participation
prematurely, 211 in the acarbose-treated group and 130 in the placebo group;
these patients were also followed up for outcome parameters. Decreasing postprandial
hyperglycemia with acarbose was associated with a 49% relative risk reduction
in the development of cardiovascular events (hazard ratio [HR], 0.51; 95%
confidence interval [CI]; 0.28-0.95; P = .03) and
a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction
was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P = .02). Acarbose was also associated with a 34% relative
risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95%
CI, 0.49-0.89; P = .006) and a 5.3% absolute risk
reduction. Even after adjusting for major risk factors, the reduction in the
risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P = .02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P = .004) associated with acarbose treatment was still statistically
significant.

Conclusion This study suggests that treating IGT patients with acarbose is associated
with a significant reduction in the risk of cardiovascular disease and hypertension.

Cardiovascular disease (CVD) is the leading cause of death among individuals
with type 2 diabetes mellitus, accounting for 40% to 50% of all deaths.1 In these patients, the mortality risk for coronary,
cerebrovascular, and peripheral vascular disease is 2-fold to 10-fold higher
than in the nondiabetic population.2- 4 Although
type 2 diabetes is frequently associated with other cardiovascular risk factors,
such as dyslipidemia and hypertension,5,6 it
is believed that hyperglycemia per se is an independent risk factor.6 More recently, special emphasis has been given not
only to fasting but more particularly to postprandial hyperglycemia as a risk
factor for CVD in patients that do not have diabetes as well as those who
have it.7- 9

It is now believed that macrovascular disease starts before the development
of diabetes.10 Several studies have now confirmed
the increased risk of CVD in patients with impaired glucose tolerance (IGT)
even after adjusting for classic risk factors.11- 15 The
moderate increase in postprandial plasma glucose levels in patients with IGT
was shown to be an independent predictor for CVD. More recently, using ultrasonography
to measure carotid intimamedia thickness, it was shown that postchallenge
plasma glucose was a strong predictor of atherosclerosis.16- 21

In the STOP-Noninsulin-Dependent Diabetes Mellitus (NIDDM) trial, we
demonstrated that decreasing postprandial plasma glucose levels in patients
with IGT with acarbose, an α-glucosidase inhibitor, could reduce the
risk of diabetes.22 Another important objective
of the study was to test whether decreasing postprandial hyperglycemia would
also diminish the risk of CVD and hypertension.

METHODS

The STOP-NIDDM Trial was an international, double-blind, placebo-controlled,
randomized study undertaken in hospitals in Canada, Germany, Austria, Norway,
Denmark, Sweden, Finland, Israel, and Spain. Details of the study design and
methods have been described elsewhere.22,23

Participants were recruited (starting in December 1995; recruitment
was closed in July 1998) from a high-risk population of men and women between
the ages of 40 and 70 years with a body mass index (BMI), calculated as weight
in kilograms divided by the square of height in meters, between 25 and 40.
They were eligible for the study if they had IGT according to the World Health
Organization criteria,24 plus a fasting plasma
glucose concentration of between 100 and 140 mg/dL (5.5 and 7.8 mmol/L). Patients
were excluded if they had had any cardiovascular event within the last 6 months.

Eligible patients were randomized to receive placebo or 100 mg of acarbose
3 times a day, taken with the first bite of each meal. Randomization was done
using a computer program allocation sequence that was stratified by center.22 Randomization was done in blocks of 4 and 6 to minimize
the chance that the investigators could guess the treatment assignment. Numbered
drug containers were used to implement the random allocation process. Since
the random code was stratified by center, the patients were randomized sequentially
at each center. The random codes were concealed in 3-part container labels
that were stored separately in the event that the investigator needed to know
the treatment of a patient. The allocation sequence was generated by an independent
statistician who was a member of the data safety and quality review committee.23 Enrollment and randomization was handled at the sites.
The study was completed in August 2001 after a mean (SD) follow-up of 3.3
(1.15) years.

All patients were instructed to go on a weight-reduction or weight-maintenance
diet and were encouraged to exercise regularly; these instructions were reinforced
at each visit. Participants were examined every 6 months by the investigator
and seen every 3 months by the coordinating nurse for pill count and distribution,
documentation of adverse events, and measurement of blood pressure and fasting
plasma glucose concentration. They were asked to remain in the study until
the last randomized patient had been treated for 3 years. The protocol was
approved by appropriate institutional review boards, and each patient signed
an informed consent form.

Part of the study protocol included evaluating the effect of acarbose
on the occurrence of CVD. The main outcome measure was the number of patients
developing major cardiovascular events, including coronary heart disease (myocardial
infarction, new angina, revascularization procedures), cardiovascular death,
congestive heart failure, cerebrovascular events, and peripheral vascular
disease. Myocardial infarction was defined as clinical symptoms of myocardial
ischemia with elevated serum cardiac enzymes and electrocardiographic changes;
at least 2 of these 3 criteria had to be present for the clinical diagnosis.
The diagnosis of silent myocardial infarction was based on new Q waves and
prolonged ST-segment elevation on at least 2 contiguous leads. New angina
was defined as ischemic cardiac pain with diagnostic exercise electrocardiographic
or stress perfusion imaging findings compatible with myocardial ischemia.
Cardiovascular death was death due to congestive heart failure, myocardial
infarction, cerebrovascular event, cardiovascular procedures, pulmonary embolism,
or sudden death. Congestive heart failure was defined as recent onset of new
or aggravation of symptoms compatible with heart failure with supportive documentation
such as chest radiograph or electrocardiographic changes. Cerebrovascular
events related to the presence of neurological deficits such as transient
ischemic attack or stroke. Peripheral vascular disease was diagnosed based
on the development of intermitted claudication with clinical vascular disease
confirmed by doppler or angiography. These events were ascertained by an independent
adjudicating committee of 3 cardiologists blinded to treatment. According
to the protocol, all patients had undergone an electrocardiogram before being
randomized and at the end of treatment. These were read by 2 independent cardiologists
who were also blinded to treatment.

The effect of acarbose on the development of new cases of hypertension
was another secondary objective. Hypertension was defined as blood pressure
of at least 140/90 mm Hg on 2 consecutive visits or if the family physician
added antihypertensive medication between visits. Blood pressure was measured
by the coordinating nurse with the patient in the sitting position and a mean
of 3 measurements was used.

Plasma glucose concentration was measured in local laboratories by the
glucose oxidase or hexokinase method. Plasma insulin and lipid profiles were
quantitated in 2 central laboratories, one in Toronto, Ontario, the other
in Dresden, Germany. Plasma insulin was measured by highly specific immunoradiometric
assay with a 2-site monoclonal antibody.25 Serum
triglyceride levels, total cholesterol, and high-density lipoprotein cholesterol
concentrations were measured enzymatically. Low-density lipoprotein cholesterol
was calculated mathematically if the triglyceride concentration was less than
400 mg/dL (4.51 mmol/L) using the Friedwald formula.26,27 Cross-checked
validation for various measurements was done every 4 months for all participating
laboratories.23

Sample-size calculation was based on the primary end point: the development
of diabetes. It was estimated that 600 patients would be required in each
treatment group for a 2-tailed α of .05 and a 1−β of 90%
assuming a conversion rate of 7% per year, a 36% risk reduction, and a drop-out
rate of 10%.23

The cardiovascular end points and the development of hypertension were
analyzed according to a modified intent-to-treat analysis excluding those
who did not meet the IGT criteria (n = 17) and those who did not have any
valid postrandomization data (n = 44). The primary variables were time to
development of cardiovascular events and hypertension, for which we used survival
analysis to compare the 2 treatment groups. Formal analysis was performed
using the Cox proportional hazards model of the SAS software version 8.2 (SAS
Inc, Cary, NC). A stratification variable was added to the Cox proportional
hazards model to adjust for possible regional (ie, country) differences and
homogeneity within regions and to better ensure that the assumption of proportionality
was maintained in the model. The assumption of proportionality for the Cox
proportional hazards models were informally assessed with a combination of
log (−log [survival]) vs log (survival time) graphs to assess parallelism
in the primary models. Linear hypothesis tests used the Wald χ2 statistic.
We also tested, with the Kaplan-Meier method, the probability of survival
outcome. The effect of treatment on the overall incidences of cardiovascular
events and hypertension was assessed by multivariate analysis using the Cox
proportional hazards model adjusting for the following baseline variables:
fasting and 2-hour plasma glucose and plasma insulin concentrations; glycated
hemoglobin A1c levels; total, high-density lipoprotein, and low-density
lipoprotein cholesterol levels; triglyceride levels; systolic and diastolic
blood pressure; heart rate; body weight; BMI; waist circumference; concomitant
medications (except for hypertension); and smoking status. Specifically, these
parameters were assessed individually in univariate models and, in turn, tested
in a multivariate model if P was less than .25. A
forward-selection process was then used, whereby parameters were kept in the
multivariate model only if it was statistically significant at the 5% level.
We further assessed changes over time in those same variables using a repeated-measure
analysis of variance model up to 3 years after randomization. Fisher exact
tests were also used for some analyses to assess actual incidences of events
between various treatment groups.

RESULTS

Overall, 1429 patients were randomized to receive either acarbose (n
= 714) or placebo (n = 715). We excluded 61 patients who did not meet the
criteria for IGT (9 receiving acarbose; 8 receiving placebo) or those who
had no valid postrandomization data (23 receiving acarbose; 21 receiving placebo).
This left 1368 patients, 682 patients in the acarbose group and 686 patients
in the placebo group (Figure 1).
The mean (SD) follow-up time was 3.3 (1.2) years.

Twenty-four percent discontinued their participation prematurely, mostly
during the first year (211 in the acarbose group and 130 in the placebo group).
The most common reason for discontinuation was adverse gastrointestinal tract
effects, such as flatulence, diarrhea, and abdominal pain. These patients,
however, were followed up for outcome variables. Forty-three (3%) could not
be followed up for measurements of end points. Both study patients and investigators
were asked to guess the treatment assignment at the end of the study; 48%
of patients receiving placebo and 79% receiving acarbose thought they were
taking the active drug. Physicians guessed use of acarbose correctly in 69%
and incorrectly in 31% of the cases and guessed use of placebo correctly in
64% and incorrectly in 36% of the cases.

The demographic and biochemistry data are listed in Table 1. There was no difference between the 2 treatment groups
in experience of and treatment for CVD (Table 1). The baseline characteristics of the 44 patients who were
excluded for lack of postrandomization data were similar to the overall study
population and were similar between groups. The mean (SD) age was 55.4 (8.0)
years with a BMI of 31.7 (4.2), and a waist circumference of 107.1 (12.6)
cm. In this excluded group, 11.4% smoked, and 34% took cardiovascular medications.

Figure 2 shows that acarbose
treatment increased the probability of remaining free of any cardiovascular
event (P = .04 by log-rank test). Using the Cox proportional
hazards model, treatment with the α-glucosidase inhibitor vs placebo
was associated with a significant risk reduction of developing any cardiovascular
event with a hazards ratio (HR) of 0.51 (95% confidence interval [CI], 0.28-0.95; P = .03). The assumption of proportionality was satisfied
in this model with parallelism of the log (−log [survival]) vs log (survival
time) graph, as well as a nonsignificant P value
in the hypothesis test of linearity (Wald χ2, P = .24).

Altogether, 47 patients had at least 1 cardiovascular event, 32 in the
placebo-treated and 15 in the acarbose group (Figure 3). This gives a cumulative incidence of 4.7% in the placebo
group for an annual incidence of 1.4%. Acarbose treatment was therefore associated
with a relative risk reduction of 49% and an absolute risk reduction of 2.5%.
Furthermore, 72% of the patients with cardiovascular events (22, placebo group;
12, acarbose) experienced a cardiovascular event during the IGT stage before
they had developed diabetes (or did not develop diabetes at all during the
study), while only 28% (10, placebo; 3, acarbose) experienced an event after
onset of diabetes. There were 13 clinical cases of myocardial infarction,
12 occurring in the placebo group so that the difference was significant (HR,
0.09; 95% CI, 0.01-0.72; P = .02). Electrocardiographic
results confirmed an additional 8 silent myocardial infarctions that were
not found clinically; 1 was in the acarbose-treated group vs 7 in the placebo-treated
group (P = .07, Fisher exact test). If these are
included with the clinical cases of myocardial infarction, the cumulative
incidence of myocardial infarctions in patients taking acarbose would have
been 2 and would have been 19 for those taking placebo (P <.001, Fisher exact test). The effect of the study medication
on the other individual cardiovascular events was not significant because
of the small number of events, but the trend consistently favored acarbose
treatment (Figure 3).

Acarbose treatment also had a significant effect on the risk of developing
hypertension (Figure 4; P = .007 by the log-rank test). Only 78 patients (11%) of 682 in the
acarbose group developed hypertension vs 115 (17%) of 686 in the placebo group
(HR, 0.66; 95% CI, 0.49-0.89; P = .006). This gives
a relative risk reduction of 34% and an absolute risk reduction of 5.3% associated
with acarbose treatment. Table 3 shows
that among the various baseline clinical and metabolic parameters, only systolic
and diastolic blood pressure (P<.001; P = .002, respectively) were positively associated with the risk of
hypertension on univariate analysis. On multivariate analysis, only acarbose
treatment (P = .004) and diastolic blood pressure
(P<.001) remained independent factors. The assumptions
of proportionality were satisfied in these Cox proportional hazards models.

This is the first prospective intervention study testing the postprandial
hyperglycemia hypothesis as a risk factor for CVD. The data show that treatment
with the α-glucosidase inhibitor acarbose was associated with a significant
reduction in cardiovascular events in a population with IGT characterized
by moderate postprandial hyperglycemia.

Although the STOP-NIDDM trial was not initially powered to answer that
question, the analysis of the data using the Cox proportional hazards and
the log-rank test showed that acarbose treatment was associated with a significant
reduction in cardiovascular events. The incidence of cardiovascular events
in the STOP-NIDDM trial population with IGT was 1.4% per year based on the
placebo-treated group. These events were ascertained and confirmed by an independent
adjudicating committee blinded to treatment. The incidence observed in the
present study was not very different from other reports, which showed that
cardiovascular mortality in IGT populations varied between 0.4% and 0.9% per
year.11,29- 31 Since
the incidence of cardiovascular events would be expected to be higher than
the mortality rate, our observation of 1.4% per year was not unexpected. Thus,
in the STOP-NIDDM trial, the incidence of cardiovascular events in the placebo
group is what would be expected; the lower-incidence in the acarbose group
(0.7% per year) would suggest a treatment effect.

Overall, 84 clinical cardiovascular events were documented throughout
the study occurring in 47 patients; 32 patients (4.7%) were in the placebo
group vs 15 (2.2%) in the acarbose group (P = .03).
Myocardial infarction by itself was statistically significantly more frequent
in the placebo group whether we include the silent myocardial infarctions
(19 vs 2; P<.001 by Fisher exact test) or not
(12 vs 1; P = .02 by Cox proportional hazards analysis; Figure 3). Although the other events taken
individually were not significant due to the small numbers, they consistently
favored acarbose (Figure 3). Even
after adjusting for all other measured risk factors at baseline, the acarbose
treatment was still associated with a significant reduction in the risk of
CVD (P = .02; Table 2). Acarbose treatment was therefore associated with a relative
risk reduction of 49% for cardiovascular events and an absolute risk reduction
of 2.5% among IGT patients. The number needed to treat to prevent 1 cardiovascular
event would be 40 patients with IGT over 3.3 years.

The incidence of new cases of hypertension in placebo-treated patients
with IGT was 10% per year. Although there are few data on the incidence of
hypertension among patients with IGT, the observed incidence in the present
study is higher than expected. In The San Antonio Heart Study, Haffner et
al32 found an increased risk of hypertension
only in women with IGT, for which the hazard ratio was 1.94 with an annual
incidence of 1.5%. However, the diagnostic criterion for hypertension in that
study was blood pressure of 160/90 mm Hg or higher. In the STOP-NIDDM trial,
the most recent criterion for hypertension of 140/90 mm Hg or higher was used.
Furthermore, the San Antonio Heart Study population was much younger, being
evenly distributed between the ages of 25 and 64 years. In addition, it was
a population-based study while our participants were selected from a high-risk
population at baseline. Acarbose significantly reduced the mean systolic and
diastolic blood pressure throughout the study period (Figure 5). But, more important, it significantly decreased the risk
of developing hypertension. Based on the recent diagnostic criteria, 193 new
cases of hypertension were diagnosed during the study period; 115 (33.7% per
3.3 years) occurred in patients treated with placebo vs 78 (24% per 3.3 years)
patients in the acarbose-treated group (P = .006).
Even after adjusting for other risk factors at baseline, the acarbose treatment
effect on the risk of hypertension remained significant and independent (P = .004; Table 3).
Acarbose treatment thus resulted in a relative risk reduction of 34% for the
development of hypertension and in an absolute risk reduction of 5.4%. The
number needed to treat to prevent 1 case of hypertension would be 19 IGT patients
for 3.3 years. Since hypertension is itself a risk factor for CVD, such an
intervention would be highly cost-effective.33 We
are not aware of any other prospective intervention studies that have looked
at the prevention of hypertension in high-risk populations.

The STOP-NIDDM trial is the first prospective intervention study demonstrating
that treatment with acarbose in IGT patients is associated with a lower incidence
of CVD and hypertension. The intriguing question is: what is the relationship
between acarbose and the reduction of postprandial hyperglycemia and the observed
lower incidence of CVD and hypertension? Although the present study was not
designed to answer that question, some observations from this trial can offer
potential leads. Acarbose treatment was associated with a significant reduction
in body weight, BMI, and waist circumference, in blood pressure, in 2-hour
plasma glucose concentration, and in triglyceride levels. All of these factors
have already been shown to be associated with an increased risk of CVD and
hypertension.9,16,34- 36 In
the STOP-NIDDM trial, the patients who developed CVD had a significantly larger
waist circumference (105.5 vs 102.1 cm) and higher blood pressure (139.5/86.3
vs 130.9/82.3 mm Hg) at baseline compared with those who did not. On multivariate
analysis, baseline blood pressure, even within the normal range, remained
a significant predictor of CVDs and hypertension (Table 2 and Table 3).
Furthermore, acarbose treatment resulted in a significant decrease in blood
pressure (Figure 5). Although all
those factors could explain, in part, the beneficial effect of acarbose on
CVD and hypertension, the effect of α-glucosidase inhibitor treatment
on those outcomes remained statistically significant and independent after
adjusting for those variables (Table 2 and Table 3). However, other unknown
mechanisms such as the effects of acarbose on glucagonlike peptide 1 could
be involved.37,38

The effect of postprandial plasma glucose itself remains difficult to
evaluate. The 2-hour plasma glucose concentration after 75 g of glucose is
not directly affected by acarbose and, under these conditions, is not a good
surrogate for the effect of the drug on postprandial plasma glucose concentration.
A test meal would have been useful. However, we have already shown that acarbose
could normalize postprandial plasma glucose concentration after a meal in
patients with IGT.39 In this context, Ceriello
et al40- 43 have
already shown that postprandial hyperglycemia concentration is associated
with an increase in oxidative stress. This is true in normal individuals,
in IGT patients, as well as in patients with diabetes.44,45 It
has also been shown that acarbose taken with meals can blunt this increase
in oxidative stress.43 Postprandial oxidative
stress is also associated with endothelial dysfunction, which has been suggested
to be involved in the development of both hypertension and CVD.46- 48 All
of these observations make a reduction in oxidative stress an interesting
mechanism by which acarbose could mediate, at least in part, its beneficial
effect on the prevention of both CVD and hypertension. A definite cause-and-effect
relationship, however, remains to be established.

We acknowledge the limitations in the interpretation of the cardiovascular
data from the STOP-NIDDM trial. First, the intent-to-treat population is modified
by excluding the 61 patients whose postrandomization data was unavailable
because they had dropped out of the study immediately after being randomized
without taking any study medications. Second, the study was powered for incidence
of diabetes, not for CVD, which was an a priori secondary objective. Third,
the analysis was not adjusted for multiple testing, and because of the small
number of events, the possibility that the observed effect could be due to
chance cannot be ignored. Fourth, premature discontinuation was higher than
expected, 211 in the acarbose group vs 130 in the placebo group. However,
the demographic and biochemistry data in the dropout population were identical
to the overall study population. Moreover, those who had dropped out were
followed up for outcome parameters and 9 patients randomized to receive placebo
had a cardiovascular event compared with 4 of those randomized to received
acarbose. Fifth, 79% of patients and 69% of physicians guessed correctly about
treatment assignment. Although guessing could effect the outcome, certainty
was only obtained retrospectively. In fact, of the 869 patients who thought
they were taking acarbose, 329 (38%) were taking placebo. It is very unlikely
that it could explain a 50% difference in cardiovascular events. Nonetheless,
despite all these limitations, there is a consistency in the effect of acarbose
on overall cardiovascular events and on myocardial infarctions, both clinical
and silent. We believe that these observations are statistically and clinically
significant. They are, however, hypothesis-generating and will need to be
confirmed.

In conclusion, The STOP-NIDDM trial is the first prospective intervention
study showing that treatment with an α-glucosidase inhibitor in IGT
patients is associated with a significant reduction in the incidence of CVD
and hypertension. These observations are compatible with the hypothesis that
postprandial hyperglycemia is a risk factor for CVD and provide further arguments
for screening and treating patients with IGT.

World Health Oganization. Definition, Diagnosis, and Classification of Diabetes
Mellitus and Its Complications: Report of a WHO Consultation. Part I: Diagnosis and Classification
of Diabetes Mellitus.Geneva, Switzerland: World Health Organization; 1999.

Friedwald WT, Levy RJ, Frederickson DS. Estimation of concentration of low-density lipoprotein cholesterol
in plasma without the use of the preparative ultracentrifuge. Clin Chem.1972;18:499-502.PubMed